Human parvovirus B19 causes well described clinical disease. The association of parvovirus B19 infection with well known but previously considered idiopathic disease qualifies B19 as an ~emerging~ pathogen. The long-term goal of the applicant is a better understanding of the role of B19 infection in the etiology and pathogenesis of liver disease, including acute fulminant liver failure, and the potential role B19 virus may play in the accelerating progression of chronic liver disease to liver failure. Study of B19 virulence factors has been hampered by the lack of an efficient culture system in which B19 virus may be readily grown and by the absence of an animal model in which to study B19 infection and host response. The severe-combined immunodeficiency (SCID mouse reconstituted with human lymphoid cells (SCID-hu) has been used as a small animal model of human virus infections, such as human immunodeficiency virus. The goal of this project is to develop a small animal model in which to identify viral determinants of B19 virulence and tissue tropism. The specific aims are as follow: (1) to establish a model for wild type B19 infection in SCID-hu/BM mice. The applicants will determine routes of wold type B19 infection, tissue tropism, organ-specific viral load, and clinical manifestations of infection; (2) to determine the ability of wold type B19 infection in SCID- hu/BM mice to generate B19 variants, including sequence variants identified in acute fulminant liver failure patients, and defective viral particles; and (3) to determine the ability of B19 isolates associated with various clinical syndromes, including fulminant liver failure isolates, to infect SCID-hy/BM mice and identify clinical manifestations of variant B19 virus infection in the model. This research will help test the hypotheses that parvovirus B19 is a previously unrecognized cause of acute liver failure and that this common community acquired viral infection may act as an accelerating factor in the progression of chronic liver disease to liver failure. In preliminary studies the applicants identified variants in B19 positive liver samples with non-conserved mutations or insertions in the non-structural gene, NS1. The NS1 has deoxyribonucleic acid (DNA) binding properties and helicase activity, and is known to upregulate transcription from viral promoters. The applicants have made the hypothesis that hepatotropic B19 bariants express mutant NS1 with increased cytotoxicity. The investigators will employ molecular virological and cell culture methods to test their hypotheses.